The present invention relates to a series of new prostaglandin derivatives, which have a variety of valuable therapeutic activities, and provides processes for preparing these compounds and methods and compositions using them.
The prostaglandins generally are known to have a variety of valuable physiological activities and a variety of prostaglandin derivatives, particularly the carbacyclins and analogs thereof, have been used for proposed to be used for the treatment of thrombosis or related conditions as a result of their valuable ability to inhibit the aggregation of blood platelets.
The compound known by the trivial name "carbacyclin" is described, for example, in UK Patent Specification No. 2,012,265, which describes and claims a series of compounds which may be represented by the formula (A): ##STR1## Carbacyclin is one of the isomers of the compound having this formula (A) in which a is 3 and R.sup.a represents a pentyl group. It should be noted that the .alpha.-side chain of this compound [the chain of formula HOOC--(CH.sub.2).sub.a --CH.dbd.] contains an exo double bond (i.e. a double bond outside the bicyclooctane parent structure).
Subsequently, certain compounds having a related structure, which may be represented by the formula (B): ##STR2## (where R.sup.1, R.sup.4, R.sup.5, R.sup.7 and B represent groups similar to those defined hereafter in relation to the compounds of the invention and b represents an integer from 1 to 6) were disclosed in U.S. patent application Ser. No. 634,351 filed July 25, 1984 abandoned in favor of Ser. No. 930,030, filed Nov. 7, 1986. Somewhat similar compounds are disclosed in a PCT Publication WO84/02902.
The compounds of formula (B) and similar compounds may be referred to as "isocarbacyclin" derivatives in that they can be isomeric with carbacyclin derivatives but, whereas the carbacyclin derivatives have an exo double bond in the .alpha.-side chain, the isocarbacyclin derivatives have an endo double bond (i.e. a double bond within the bicyclooctane system) at either the 2-position or the 3-position (indicated by the dotted line) of the bicyclooctane system. Certain of these isocarbacyclin derivatives have better physiological activity than do the known carbacyclin derivatives.
Although many chemical modifications have been made to the .omega.-side chain [i.e. the side chain at the 6-position of the bicyclooctane system, for example that represented by --B--CH(R.sup.7)--OR.sup.5 in formula (B)] and although some modifications have been made in the substituent [e.g. that represented by R.sup.1 in formula (B)] at the terminal position of the .alpha.-side chain, the prior art compounds--not only the closest prior art referred to above but also other, more remote, prostaglandin derivatives--generally have one thing in common: the .alpha.-side chain is a straight (unbranched) chain of carbon atoms or simply has a methyl branch and chemical modifications made to this chain have generally been relatively minor.
We have now surprisingly discovered that the introduction of a methylene or substituted methylene group at the .alpha.-carbon atom of this chain produces a series of prostaglandin derivatives which have extremely valuable physiological activities, such as vasodilating activity, bronchodilating activity, cell-protecting activity and, in particular, a strong inhibitory activity against blood platelet aggregation and a strong anti-ulcer effect.